Production of 11 C-methyl iodide

ABSTRACT

The present invention discloses a method and an apparatus for high yield production of  11  C-methyl iodide by selectively monohalogenating  11  C-methane, whereby the method is comprising a first step of introducing  11  CH 4  into an apparatus containing a circulation system comprising a number of connected circulation members (1-7), and the circulation system is further comprising a number of valves (V114 V5) and at least one pump (8) for controlling the circulation. The method further comprises a second step of recirculation of  11  CH 4  and introduction of iodine vapor into the circulating gas stream passed through a heated reaction chamber (3) within the apparatus having the circulation system during a predefined time period during continuous removal of formed  11  CH 3  I by means of a second trap (7), and a third step of releasing after the predefined time period the produced  11  C-methyl iodide for further processing by heating the second trap (7) containing the produced  11  CH 3  I while leading a stream of inert gas through the second trap, whereby this second trap (7) will act as a small size chromatograph purifying the desired  11  CH 3  I.

This application is a 371 of PCT/SE95/01247 filed Oct. 20, 1995.

TECHNICAL FIELD

The present invention relates to a method and a system for production ofthe positron emitting compound ¹¹ C-methyl iodide in high yields, withgood radiochemical purity and high specific activity.

PRIOR ART

A group of medical diagnostic procedures utilize radioactive labeledcompounds. This principle is also used for the diagnostic procedure PET(Positron Emitting Tomography), where the radioactive atoms are positronemitters. Some examples of positron emitting elements include nucleidsof carbon (C), oxygen.(O), nitrogen (N) or fluorine (F). These elementsare the backbone of almost all biological active compounds. To be ableto use the method stable isotopes are replaced with a radioactiveisotope. The radioactive labeled compounds, called tracers, aretransported, accumulated and converted exactly the same way as for thenon-radioactive compound. The PET method has possibilities to detectmalfunction on a cellular level in the investigated tissues or organs.The method is very sensitive and requires only nanomole quantities ofproduced radioactive tracers. The half-life of these radioactive tracersrange from 2 to 110 minutes and the production of the radioactivenucleids as well as the biological active tracer has to take place justprior to the use of it. The radioactive nucleids are produced in anaccelerator and immediately processed to small molecules. These smallmolecules react with larger non-radioactive building blocks to yield thedesired tracer.

One important and very useful starting compound is carbon-11 labeledmethyl iodide (¹¹ C--CH₃ I). Carbon is the most frequent type of atom inbiological active compounds and pharmaceuticals. With ¹¹ C-labeledmethyl iodide it is possible to make a large variety of ¹¹ C-labeledcompounds. These are of interest for diagnosis and follow up of atreatment of, for example, cancer, epilepsy or dementia.

Such a compound is today most often formed from ¹¹ C-labeled carbondioxide (¹¹ CO₂) through reduction with lithium aluminum hydride (LAH)to ¹¹ C-labeled methanol and a reaction of this compound with hydrogeniodide to produce ¹¹ C-labeled methyl iodide. The reaction takes placein an organic solvent. This method has several disadvantages; thechemicals are cumbersome to use which makes the process unreliable andthe LAH contains a variable amount of cold carbon dioxide lowering therelation between produced radioactive and non-radioactive ¹¹ C-labeledmethyl iodide. In many investigations is it desirable to have a highratio.

Another way to produce this compound is the halogenation of ¹¹ C-labeledmethane (¹¹ CH₄) with iodine. The ¹¹ CH₄ is formed from the catalyticreduction of ¹¹ C-labeled carbon dioxide. The halogenation reaction ofthe ¹¹ CH₄ is a non-selective radical reaction taking place underelevated temperatures. As iodine always will be present in a largeexcess it is difficult to prevent polyhalogenation, leading to lowradiochemical purity. In the published literature mixtures betweenmono-, di-, tri- and tetra-iodinated methane are formed (LIT REF). Ifthe reaction conditions are suitable for formation of only themono-halogenated compound in high purity, the yields are low (<10%) dueto the very short reaction time necessary to prevent furtherhalogenation.

DISCLOSURE OF THE INVENTION

The present invention solves the problem of the low chemical yields andlow radio chemical purity of the radical iodination reaction. Thereaction time and temperature are optimized to give a puremono-halogenated methyl iodide. The small fraction of formed ¹¹C-labeled methyl iodine is removed from the gas mixture, and theremaining ¹¹ C-labeled methane is purified and recirculated. Freshiodine is added and the process is repeated until the conversion of the¹¹ CH₄ is complete.

According to a first object of the present invention a method forproduction of ¹¹ C-methyl iodide is disclosed by selectivelymonohalogenating ¹¹ C-methane, whereby the method is comprising a firststep of introduction of ¹¹ CH₄ into a circulation system comprising anumber of connected circulation members, and the circulation system isfurther comprising a number of valves and at least one pump forcontrolling the circulation, a second step of recirculation of ¹¹ CH₄and introduction of iodine vapors into the circulating gas stream passedthrough at least one heated reaction chamber within the circulationsystem during a predefined time period during continuous removal offormed ¹¹ CH₃ I by means of the second trap, and a third step ofreleasing the produced ¹¹ C-methyl iodide after the predefined timeperiod for further processing by heating the second trap containing theproduced ¹¹ CH₃ I while leading a stream of inert gas through the secondtrap, whereby this second trap will act as a small size chromatographpurifying the desired ¹¹ CH₃ I.

According to a second object of the present invention an apparatus forproduction of ¹¹ C-methyl iodide is disclosed by selectivelymonohalogenating ¹¹ C-methane, whereby the apparatus for application ofthe method is comprising a recirculation system including a first trap,an iodine chamber, at least one heated reaction chamber, a condensationchamber and a trapping chamber, a second trap and at least one pump,whereby the recirculation system further is comprising a number ofvalves for controlling the circulation and the second trap by means of asuitable contained material, or being a cold trap, will with a highyield trap and store the produced ¹¹ C-methyl iodide to be released forfurther processing by heating this second trap containing the produced¹¹ CH₃ I.

Further embodiments of the method and the apparatus for utilizing themethod are additionally defined by the dependent claims 2-6 and 9-12,respectively, in the attached set of claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described by preferred embodiments to becontemplated with reference to the accompanying drawings wherein likereference numerals are used throughout to designate like parts. In thedrawings:

FIG. 1 shows an embodiment of a system including a ¹¹ C-methane sourcein the recirculation system and utilizing the method according to thepresent invention; and

FIG. 2 shows an other embodiment of a system having to the recirculationsystem an external ¹¹ C-methane source and utilizing the methodaccording to the present invention.

DESCRIPTION OF EXEMPLIFYING EMBODIMENTS

FIG. 1 demonstrates a first embodiment of an apparatus for performingthe process according to the present invention. The apparatus of FIG. 1contains a closed recirculation circuit comprising a trap 1, for examplea cold trap or a molecular sieve trap, as a source of ¹¹C-methane+nitrogen which is included in the circuit through two valvesV1 and V2, respectively. Instead of nitrogen any other inert gas may beutilized. Additionally in the closed circuit there is an iodine source2, a reaction chamber 3, a condensation zone 5, an ascarite trap 6, aCH₃ I-trap 7 and a pump 8. The iodine source 2 is a quartz tube whereiodine vapors are created by suitable heating of iodine crystals. Thereaction chamber 3 is heated by an oven 4. This chamber 3 may alsocontain a suitable catalyst for the reaction producing ¹¹ C-methyliodide by selectively monohalogenating ¹¹ C-methane. After the chamber 3there is a condensation zone 5, to retrieve into solid form iodinevapors not consumed by the process in the reaction chamber 3. After thecondensation zone 3 there is a trap 6 which in a preferred embodiment iscontaining ascarite and where HI, ¹¹ CO₂ and the rest of the iodine willbe trapped. After the trap 6 there is another trap which adapted toremove and store the produced methyl iodide from the recirculating gas.The recirculation of gas in the system is achieved by means of at leastone pump. Between the second trap 7 and a pump 8 there are additionalvalves V3, V4 and V5. Valves V4 and V5 may be switched to let outproduced and stored ¹¹ C-methyl iodide from the trap 7. Valve V3 is usedfor adding inert gas, for example helium, into the system as will bediscussed below.

In FIG. 2 is demonstrated in a second embodiment an alternativeapparatus for performing the process according to the present invention.The apparatus of FIG. 2, similar to the apparatus of FIG. 1, contains atrap 1, for example a cold trap or a molecular sieve trap, an iodinesource 2, a reaction chamber 3, a condensation zone 5, an ascarite trap6, a CH3I-trap 7 and a pump 8. The difference from FIG. 1 is that thetrap 1 is not a part of the recirculation system, but the closedcirculation is achieved by means of switching open the passage betweenvalves V4 and V3. In the apparatus of FIG. 2 the inert gas like heliumis inserted through valve V2, while in FIG. 1 the inert gas is insertedthrough valve V3. In the apparatus of FIG. 2 all valves V1, V2, V3, V4,and V5 are placed between the second trap 7 and the pump 8. In bothembodiments of FIG. 1 and FIG. 2 when the trap 1 is a cold trap it ispreferably cooled by means of a liquid having a boiling point of below-162° C. The second trap 7 may be heated by a heater 10 for release oftrapped CH3I via valves V4 and V5. Valve V5 is used to direct the outputeither as a waste or as output of the desired product.

The procedure according to the present invention for production of ¹¹C-methyl iodide by selectively monohalogenate ¹¹ C-methane may bedivided into three step as described below.

Step 1: Introduction of ¹¹ CH₄ into the Recirculation System

It is essential to the synthesis that the system is loaded with pure ¹¹CH₄ in a pure inert gas.

¹¹ CH₄ in N₂ could be produced in the target by irradiation of a mixtureof N₂ and H₂ with photons, or the ¹¹ CH₄ could be produced outside thetarget by catalytic or non catalytic reduction of ¹¹ CO₂ or ¹¹ CO in N₂.

The purification and concentration of the ¹¹ CH₄ is done by leading thegas mixture through a trap 1 filled with Porapak N. and cooled in liquidN₂ (FIG. 1 and 2). In this trap 1 the methane is retained and theimpurities are swept through. After the trapping the ¹¹ CH₄ is releasedinto a stream of helium, He, by moving the trap from the cooling bath.If the trap 1 is placed inside the recirculating part of the system(FIG. 1) the ¹¹ CH₄ is now in place and the recirculation can begin. Ifthe trap is placed outside the recirculating part of the system (FIG. 2)the ¹¹ CH₄ is loaded into the system through valves V1 and V3 in a smallvolume of, for instance, He.

As an alternative for helium, He, may be substituted any other inert gaslike Ne, Ar, Kr, Xe or another gas as for example N₂.

The cooling of a cold trap may utilize liquid nitrogen, liquid air,liquid oxygen or liquid He, Ne, Ar, etc., or solid CO₂, a coolingcompressor, a vortex tube, or the like.

In an alternative embodiment instead of using a cold trap, the ¹¹ CH₄could be trapped at a higher temperature (room temperature) an bereleased by heating. The Porapak N could be substituted by a largenumber of trapping materials. Examples of such materials are: Activatedcarbon, molecular sieves, a large number of GC packing material, plasticpowder, polymers or inorganic carriers coated with high boiling liquids,or carriers coated with chemically bonded organic molecules, and so on.

Instead of using a cold trap to capture ¹¹ CH₄, ¹¹ CO₂ produced byirradiation of N₂ containing traces of O₂ by protons, can be captured ina trap containing a mixture of molecular sieve and a catalyst (Ni, Pd,Pt, Rh, Fe, . . . ) saturated with H₂. The trap is then flushed withinert gas, closed and heated. The ¹¹ CO₂ is released from the molecularsieve and reduced to ¹¹ CH₄ by the hydrogen, H₂ on the catalyst. Thetrap is opened and the ¹¹ CH₄ is released into a stream of inert gas.

If the trap is now placed inside the circulating part of the system(FIG. 1) the ¹¹ CH₄ is now in place and the recirculation can start.

If the trap is placed outside the circulating portion of the system(FIG. 2) the ¹¹ CH₄ is loaded into the system through a valve V1 and V3in a small volume of inert gas.

Step 2: Recirculation of ¹¹ CH₄ During Continuous Removal of Formed ¹¹CH₃ I.

All valves are switched such that the pump circulates the mixture of ¹¹CH₄ and for instance He from the trap 1 into the quartz tube 2 where itis mixed with iodine vapors from the heated iodine crystals. The gasmixture is then led through a piece of quartz tube 3 heated to of theorder 720° C. by means of an electrical oven 4, whereby the iodinationof methane takes place.

After the oven the gases pass a piece of quartz tube (condensation zone5) kept at room temperature, i.e. about 20° C., where most of the excessof iodine crystallizes and then a piece of tube 6 filled with ascaritewhere impurities, mainly HI, ¹¹ CO₂ and the rest of the iodine, will betrapped. The ¹¹ C-methyl iodine is trapped in the CH₃ I-trap and theunchanged ¹¹ CH₄ will be recirculated.

The pump 8 used for circulation, which may be any type of suitabledevice, e.g., a membrane pump, rotary vane pump, piston pump, gear pump,Roots pump screw pump, peristaltic pump, or the like, could in practicebe placed anywhere in the closed circuit.

The I₂ -chamber 2, the reaction chamber 3, the condensation zone 5 andthe ascarite chamber 6 is in the preferred embodiment typically placedin a single piece of quartz tube, but could also be separate chambersmanufactured from different materials and connected to each other bymeans of tubes or hoses.

The reaction chamber should be chemically inert and able to withstandthe temperature needed to convert ¹¹ CH₄ to CH₃ I (200-1000° C.). Itcould be made from quartz, metals, alloys or ceramics. It is heated byan electrical oven, a flame or a stream of hot air. It is empty orfilled with a material that catalyses the reaction between ¹¹ CH₄ andI₂.

The condensation zone 5 can be kept at room temperature, or cooled to+20 to -100° C. by a stream of cold air, a vortex tube or any othercooling device.

The Ascarite in the Ascarite chamber 6 may be replaced by Sb, Na₂ SO₃,or strong bases such as KOH or Ca(OH)₂.

In the preferred embodiment the CH₃ I-trap 7 is typically filled withPorapak N. The trapping is carried out at room temperature, and therelease is carried out by heating to 190° C. by means of an electricaloven 10 or by a stream of hot air. This Porapak N may be substituted bya large number of trapping materials. Examples of such materials are:Activated carbon, molecular sieves, a large number of GC packingmaterial, plastic powder, polymers or inorganic carriers coated withhigh boiling liquids, or carriers coated with chemically bonded organicmolecules, and so on. The CH₃ I-trap 7 may as well be designed as acooling trap containing for example solid CO₂ in ethanol or acetone.

The trapping and release could take place between -250 and +300° C.

Step 3: Release and Purification of Trapped ¹¹ CH₃ I.

The ¹¹ CH₃ I is released by heating the trap 7, while leading a streamof helium through system and the trap. Depending on the trappingmaterial used, the trap will act as a small size chromatograph. Thiseffect can be used to get a pure product by using V5 (FIG. 1 and 2) tocollect the ¹¹ CH₃ I fraction.

The method and apparatus involving recirculation of ¹¹ CH₄ mixed forexample with helium during continuous removal of formed ¹¹ CH₃ I hasyield which is very much higher compared to prior art technique. Thetime for the recirculation process will for example be dependent of thecapacity of the pump 8, but a time of about 20 second is typical in thepreferred embodiment.

We claim:
 1. Method of production of ¹¹ C-methyl iodide by selectivelymonohalogenate ¹¹ C-methane, comprising the steps ofintroduction of ¹¹CH₄ into a circulation system including a number of connectedcirculation members, said circulation system further comprising a numberof valves means (V1-V5) and at least one pump means (8) for controllingthe circulation, recirculation of ¹¹ CH₄ and introduction of iodinevapors to the recirculating gas stream passed through at least oneheated reaction chamber means (3) within said circulation system duringa predefined time period during continuous removal of formed ¹¹ CH₃ I bymeans of second trapping means (7) containing a suitable material fortrapping of CH₃ I, release of the produced ¹¹ C-methyl iodide after saidpredefined time period for further processing by heating said secondtrapping means (7) containing the produced ¹¹ CH₃ I while leading astream of inert gas through said second trapping means (7).
 2. Methodaccording to claim 1, characterized inthat said second trapping means(7) during the release of the produced ¹¹ CH₃ I is acting as a smallsize chromatograph purifying the desired ¹¹ CH₃ I.
 3. Method accordingto claim 1, characterized inthat an iodine chamber means (2) producesvapor of iodine by means of heating iodine crystals in said iodinechamber means.
 4. Method according to claim 3, characterized inthat atrapping chamber means (6) is trapping impurities, mainly HI, ¹¹ CO₂ andthe rest of the iodine in the circulating gas after passing thecondensation chamber means (6).
 5. Method according to claim 1,characterized inthat a first trapping means (1) is prepared in advanceof the recirculation process by being flushed with inert gas, closed andheated, whereby ¹¹ CO₂ is released from a molecular sieve or a cold trapand is reduced to ¹¹ CH₄ by the H₂ on a catalyst after which said firsttrapping means is opened and ¹¹ CH₄ is released into a stream of inertgas in said recirculation system for production of ¹¹ C-methyl iodide tobe trapped in said second trapping means (7).
 6. Method according toclaims 1, characterized inthat a first trapping means (1) is preparedbefore starting the recirculation process by being flushed with inertgas, closed and heated, whereby ¹¹ CO₂ is released from a molecularsieve or a cold trap and is reduced to ¹¹ CH₄ by the H₂ on a catalystafter which said first trapping means is opened and ¹¹ CH₄ is releasedinto a stream of inert gas in said recirculation system for productionof ¹¹ C-methyl iodide to be trapped in said second trapping means. 7.Method according to claim 2, characterized inthat an iodine chambermeans (2) produces vapor of iodine by means of heating iodine crystalsin said iodine chamber means.
 8. Method according to claim 7,characterized inthat a trapping chamber means (6) is trappingimpurities, mainly HI, ¹¹ CO₂ and the rest of the iodine in thecirculating gas after passing the condensation chamber means (6). 9.Method according to claim 2, characterized inthat a first trapping means(1) is prepared before starting the recirculation process by beingflushed with inert gas, closed and heated, whereby ¹¹ CO₂ is releasedfrom a molecular sieve or a cold trap and is reduced to ¹¹ CH₄ by the H₂on a catalyst after which said first trapping means is opened and ¹¹ CH₄is released into a stream of inert gas in said recirculation system forproduction of ¹¹ C-methyl iodide to be trapped in said second trappingmeans.
 10. Method according to claim 3, characterized inthat a firsttrapping means (1) is prepared before starting the recirculation processby being flushed with inert gas, closed and heated, whereby ¹¹ CO₂ isreleased from a molecular sieve or a cold trap and is reduced to ¹¹ CH₄by the H₂ on a catalyst after which said first trapping means is openedand ¹¹ CH₄ is released into a stream of inert gas in said recirculationsystem for production of ₁₁ C-methyl iodide to be trapped in said secondtrapping means.
 11. Method according to claim 4, characterized inthat afirst trapping means (1) is prepared before starting the recirculationprocess by being flushed with inert gas, closed and heated, whereby ¹¹CO₂ is released from a molecular sieve or a cold trap and is reduced to¹¹ CH₄ by the H₂ on a catalyst after which said first trapping means isopened and ¹¹ CH₄ is released into a stream of inert gas in saidrecirculation system for production of ¹¹ C-methyl iodide to be trappedin said second trapping means.
 12. Method according to claim 5,characterized inthat a first trapping means (1) is prepared beforestarting the recirculation process by being flushed with inert gas,closed and heated, whereby ¹¹ CO₂ is released from a molecular sieve ora cold trap and is reduced to ¹¹ CH₄ by the H₂ on a catalyst after whichsaid first trapping means is opened and ¹¹ CH₄ is released into a streamof inert gas in said recirculation system for production of ¹¹ C-methyliodide to be trapped in said second trapping means.
 13. Apparatus forproduction of ¹¹ C-methyl iodide by selectively monohalogenate ¹¹C-methane, comprising a recirculation system including first trappingmeans (1), iodine-chamber means (2), heated reaction chamber means (3),condensation chamber means (5) and trapping chamber means (6), secondtrapping means (7) and pump means (8), said recirculation system furthercomprising a number of valves (V1-V5) for controlling the circulation,whereby said second trapping means (7) by means of a suitable containedmaterial is trapping and storing the produced ¹¹ C-methyl iodide to bereleased for further processing by heating said second trapping means(7) containing the produced ¹¹ CH₃ I.
 14. Apparatus for production of ¹¹C-methyl iodide by selectively monohalogenate ¹¹ C-methane, comprising arecirculation system including first trapping means (1), iodine-chambermeans (2), heated reaction chamber means (3), condensation chamber means(5) and trapping chamber means (6), second trapping means (7) and pumpmeans (8), said recirculation system further comprising a number ofvalves (V1-V5) for controlling the circulation, whereby said secondtrapping means (7) is a cold trap trapping and storing the produced ¹¹C-methyl iodide to be released for further processing by heating saidsecond trapping means (7) containing the produced ¹¹ CH₃ I. 15.Apparatus according to claim 13, characterized inthat said iodinechamber means (2) produces vapor of iodine by heating of iodine crystalsin said iodine chamber means.
 16. Apparatus according to claim 15,characterized inthat said trapping chamber means (6) is trapping HI, ¹¹CO₂ and the rest of the iodine in the circulating gas after passing saidcondensation chamber means (5).
 17. Apparatus according to claim 16,characterized inthat said first trapping means (1) is containing asuitable trapping material for ¹¹ CH₄, e.g. activated carbon, molecularsieves, a GC packing material, plastic powder, polymers or inorganiccarriers coated with high boiling liquids, or carriers coated withchemically bonded organic molecules.
 18. Apparatus according to claim16, characterized inthat said first trapping means (1) is a cold trap.19. Apparatus according to claim 14, characterized inthat said iodinechamber means (2) produces vapor of iodine by heating of iodine crystalsin said iodine chamber means.
 20. Apparatus according to claim 19,characterized inthat said trapping chamber means (6) is trapping HI, ¹¹CO₂ and the rest of the iodine in the circulating gas after passing saidcondensation chamber means (5).